Epidemiologic studies have shown that "healthy diets" marked by high intake of fruits and vegetables can reduce cancer risks at several anatomical sites. However, single dietary supplements added to lower cancer risks have produced dubious results. Therefore, we hypothesize that suboptimal concentration of agents present in healthy diets can induce optimal chemopreventive potential, if they interact in ways that generate functional synergy. We will test this hypothesis using prostate cancer as a model. Prostate cancer (CaP) is a significant cause of death in American men. Therapies that remove androgens provide relief, as does surgery. However, once the disease disseminates outside the confines of the prostate, it eventually progresses to a hormone refractory state (HRPC) which is considered unbeatable. The incidence of HRPC is lower in Asian men, compared to Caucasian males. However, Asian men who immigrated to the United States and adopted a western lifestyle have HRPC incidence rates comparable to Caucasian men. These results suggest that Asian diets contain ingredients with potential to protect against HRPC. The identity of HRPC protective agents is ill defined and their mechanism remains to be elucidated. Asian diet-based protection against HRPC may lie in functional synergism among dietary agents, generating a broadened anti-HRPC chemopreventive index with increased anticancer properties and decreased untoward effects. To test this hypothesis, we will study in this proposal combination of EGCG, genistein and quercetin, as phytochemicals present in a traditional Asian diet, for protection against HRPC. We will use CWR22Rv1 CaP cells mimicking the transition of prostate cancer from androgen dependence to HRPC. Efficacy in protection against HRPC will be determined by control of proliferation and induction of apoptosis. Functional synergism among EGCG, genistein and quercetin will be additionally validated by qualitative and quantitative differences in their molecular actions and targets, as assayed by suppression in PSA and AR expression by each agent, added in suboptimal and optimal concentrations, singly or in combination. The proposed studies will form a diet-based research framework and provide evidence of functional synergism among dietary agents. The data obtained will support the concept that combined diet-derived phytochemicals can offer easily compliant strategies for protection against HRPC. [unreadable] [unreadable] [unreadable]